Normal Physiological Barriers to the Environment::

Parenteral products are used to by-pass the normal defence mechanisms and so can offer one or more of the following Advantages: :

Parenteral products are used to by-pass the normal defence mechanisms and so can offer one or more of the following Advantages : Rapid onset Predictable + complete bioavailability Patients - Unconscious, nil by mouth, unable to swallow, uncooperative, etc. Drugs - ineffective via other routes Local effect

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What is parenteral preparation???

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British Pharmacopoeia: Parenteral preparations are sterile preparations intended for administration by injection, infusion, or injection, or implantation into the human body or animal body.

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Necessities/Ideal requirement: Sterility (must) Pyrogen (must) Free from particulate matter (must) Clarity (must) Stability (must) Isotonicity (should) Solvents or vehicles used must meet special purity and other standards. Restrictions on buffers, stabilizers, antimicrobial preservative. Do not use coloring agents. Must be prepared under aseptic conditions. Specific and high quality packaging.

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HOW to prepare parenteral product???

General steps involved in formulation:

General steps involved in formulation 1. Cleaning 2. Preparation of bulk products 3. Filtration 4. Filling of solution in or product in ampoule or vial 7. Tests for Quality control 5.Sealing 6. Sterilization All process should be performed under aseptic condition

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2.Solvents: Water Type of water Water for injection WFI (USP) Sterile Water for injection SWFI (USP) Bacteriostatic Water for injection BWFI Sterile Water for irrigation Water miscible vehicles Ethyl alcohol PEG PG Non aqueous vehicles Fixed oils

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Solvents Solvents used must be: Non-irritating Non-toxic Non-sensitizing No pharmacological activity of its own Not affect activity of medicinal Substances

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Preservatives: Multidose containers must have preservatives unless prohibited by monograph. Large volume parenteral must not contain preservative becoz it may be dangerous to human body if it contain in high doses.

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Chelating agents: Used to form the complex with the metallic ions present in the formulation so that the ions will not interfere during mfg. of formulation. They form a complex which gets dissolved in the solvents. Examples: Disodium edetate – 0.00368 - .05 % Disodium calcium edetate - 0.04 % Tetrasodium edetate – 0.01 %

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Protectants : Protect against loss of activity caused by some stress that is introduced by mfging process or to prevent loss of active ingredients by adsorption to process equipment or primary packaging materials Liposomal formulation and vaccines Examples- Cryoprotectants and Lyoprotectants Surfactants: Use in parenterals suspension and emulsionfor melting powders and to provide acceptable syringability . And solubilizing steroids anf fat soluble vitamins Examples- SLS

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Tonicity- adjusting agents: Used to reduce the pain of injection. Buffers may acts as tonicity contributor as well as stabilizers for the pH. Isotonicity depends on permeability of a living semipermaeable membrane Hypotonic : swelling of cells (enlargement) Hypertonic: shrinking of cells (reduction) Example : Glycerin Lactose Mannitol Dextrose Sodium chloride Sorbitol

Methods for Adjusting Tonicity:

Methods for Adjusting Tonicity Cryoscopic of Freezing Point Depression Method :- Body fluid such as blood plasma and lachrymal secretion fluid have freezing point of -0.52 0 c by the vertue of the different solute present in them. Hence all the solutions which freeze at -0.52 0 c will be isotonic with these fluids. %w/v of adjusting substance = 0.52-a b Where, a- depression in freezing point due to the unadjusted solution or sub. b- depression in freezing point of 1%w/v of adjusting sub.

White –Vincent Method:-:

White –Vincent Method:- This method involves the addition of sufficient quantity of water to a drug in order to prepare an isotonic solution. V= w*E*111.1 Where, V – volume in milliliter of an isotonic solution that can be prepare by dissolving w gm of drug in water E- NaCl equivalent of drug 111.1- Constant representing the volume in milliliter of isotonic solution obtained by dissolving 1g of NaCl in water Sprowls Methods:- Modified method of the white- vincent which uses tables listing the volume V of isotonic solutin that can be prepared by mixing 0.3g of a drug in water

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LABELING: Name of product Quantity of the product % of drug or amount of drug in specified volume of amount of drug and volume of liquid to be added Name and quantity of all added substances Mfg. license no. Batch no. Manufacturer/Distributor Mfg. & Expiration date Retail price (incl. of all taxes) Mfger . address Veterinary product should be so labeled

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Leakage test Fill ten containers with water. Fit with the intended closures and keep them inverted at room temperature for 24hours. There are no signs of leakage from any container. 73

Sterile products :

Sterile products Glass Ampoules : Type I (borosilicate glass is used ) Packaging is 100% tamper proof . One point or colour break ring offers consistent breaking force . Up to 3 colour can be placed for identification purpose . Package type Type of formulation can be packed Minimum quality of glass THAT can be used Ampoule Aqueous Injectables Of Any pH Type I Aqueous Injectables Of pH Less Than 7 Type II Non-Aqueous Injectables Type III 74

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1) Tip sealing - Seal is made by melting sufficient glass at the tip of the ampoule neck to form bead of the glass and close the opening. 2) Pull seals - Seals are made by heating the neck of rotating ampoule below the tip , then pulling the tip away to form small, twisted capillary prior to being melted closed Now a days, plastic ampoules for “water for injection” are available in the market. 75 Sealing of ampoule

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Vial With Stopper : Vials are mainly used for multiple dose parenteral preparation and are provided with the closure followed by aluminum seal to ensure the perfect air tight packing Vial Aqueous Injectable Of Any pH Type I Aqueous Injectables Of pH Less Than 7 Type II Non-Aqueous Injectables Type III Closure : Made from Butyl rubber ,Nitrile rubbers ,Neoprene , Silicon rubbers. It has compression recovery, coring resistance, solvent resistance, heat resistant , radiation resistance with very low water absorption and permeability properties. 76

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A) Merits Rubber is soft so that needle easily can be inserted & remove Production sterility is maintained after insertion & removal of needle because of resistance B) Demerits Sorption of active ingredient Loss of volatile compound Leaching effects 78

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Fragmentation test : Place a volume of water corresponding to nominal volume minus 4 ml in each of 12 clean vials. Close the vial with closure and secure caps for 16 hours. Pierce the closures with 21 hypodermic needle (bevel angle of 10 to 14) and inject 1 ml water and remove 1 ml air. Repeat the above operation 4 times for each closure (use new needle for each closure). Count the number of the fragments visible to the naked eye. Total numbers of the fragments should not be more than 10 except butyl rubber where the fragments should not exceed 15. 79 Test of closure

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2) Self sealability test for rubber closure applicable to multidose containers only . Fill 10 vials with water with nominal volume and close the vials with closure, secure the cap . Pierce the caps 10 times at different sites with 21 SWG hypodermic needle. Immerse the vials in 0.1% w/v methylene blue solution under reduced external pressure (27K Pa) for 10 mins . Restore the normal pressure and keep the container immersed for 30 mins . Wash the vials. None of the vials should contain trace of colored solution 3) Closure efficiency Putting liquid in pack, inverting and applying a vacuum. A poor seal is detected by liquid seeping. 80

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1 ) Leakage test for Injectable & Non-Injectable(IP 1996 ) Fill the 10 containers with water and fit the closure . Keep them inverted at RT for 24 hours . No sign of leakage from any container. 2) Water vapor permeability test for injectable preparation(IP 1996 ) Fill the 5 containers with nominal volume of water and seal. Weigh the each container . Allow to stand for 14 days at RH of 60 + 5% at 20 c to 25 c. Reweigh the container. Loss of the weight in each container should not be more than 0.2%. 87 Tests on the plastic containers

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Acidity & alkalinity test To a volume of solution corresponding to 4 per cent of the nominal capacity of the container Add 0.1 ml of phenolphthalein solution. The solution is colorless Add 0.4 ml of 0.01M sodium hydroxide. The solution is pink. Add 0.8 ml of 0.01M hydrochloric acid and 0.1 ml of methyl red solution. The solution is orange-red or red. 88

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Pre-Filled Syringe: It is used for small volume parenteral preparation. Reduction of medication errors like drug overfill . It gives Increased assurance of sterility 90

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Blow-fill-seal Technology : The basic concept of blow fill seal (BFS) is that a container is formed, filled, and sealed in a continuous process without human intervention, in a sterile enclosed area inside a machine. Plastic containers are made up of polyethylene and polypropylene . Polypropylene is more commonly used for containers because it has greater thermo stability which is further sterilized by autoclaving. 91

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A ) Thermoplastic resin is extruded into a tubular shape called a parison B) When the parison reaches the proper length, the mold is closed and the parison is cut C)The blow-fill nozzle is lowered into the parison and by blowing sterile filtered compressed air into the parison and expanding it against the walls and the sterile product is metered into the container through the fill nozzle. D) Mold comes close at the top and hermetically seal the container. E)The mold opens, and the formed, filled and sealed container is conveyed out of the machine . 92

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Sterile plastic devices : Irrigation solution container : It is made of LDPE , Polyolefin , polypropylenes Avoid hanging breakable glass It is light in weight, transparent, impermeable to water Material have high boiling point so that it is sterilizable . 93

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I.V. Infusion : It is made of acrylonitrile butadiene styrene Spike is made of nylon tube is made of polyvinyl chloride Niddle adapter is made of polymethacrilate Catheter: Catheter is inserted into a body cavity, duct, vessels. It is made of Silicone because it is inert and unreactive to body fluids and a range of medical fluids with which it might come into contact. 94

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Disposable syringe : material used are polycarbonate, polyethylene, polypropylene. Material used for piston are natural rubbers, butyl rubbers for sliding well Silicone and floroelastomer is more long lived than butyl rubbers.. They have property of abrasion resistance, radiation resistance, excellent self-life properties. 95

Preparation of Parenteral Product:

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Production facilities: Clean- up area Preparation area Aseptic area Quarantine area Finishing and packaging area Sterile area

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S T O C K R O O M COMPOUNDING AREA CLEAN UP AREA ASEPTIC AREA QUARANTINE AREA STERILIZATION STORAGE AND TRANSPORT PACKING AND LABELLING LAY OUT OF PARENTERAL MANUFACTURING AREA

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Clean- up area: Non aseptic area Free from dust, fibres & micro-organisms Constructed in such a way that should withstand moisture, steam & detergent Ceiling & walls are coated with material to prevent accumulation of dust & micro-organisms Exhaust fans are fitted to remove heat & humidity The area should be kept clean sodium that to avoid contamination to aseptic area The containers & closures are washed & dried in this area.

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Preparation area: The ingredients are mixed & preparation is prepared for filling Not essential that the area is aseptic Strict precaution is taken to prevent contamination from outside Cabinets Ceiling & walls : sealed & painted

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Aseptic area: Filtration & filling into final containers & sealing is done The entry of outside person is strictly prohibited To maintain sterility, special trained persons are only allowed to enter & work Person who worked should wear sterile cloths Should be subjected for physical examination to ensure the fitness Minimum movement should be there in this area Ceiling & walls & floors : sealed & painted or treated with aseptic solution and there should not be any toxic effect of this treatment

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Quarantine area: After filling, sealing & sterilization the products or batch is kept in this area The random samples are chosen and given for analysis to QC dept. The batch is send to packing after issuing satisfactory reports of analysis from QC If any problem is observed in above analysis the decision is to be taken for reprocessing or others..

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Finishing and packaging area: After proper label, the product is given for packing Packing is done to protect the product from external environment The ideal Packing is that which protects the product during transportation, storage, shipping & handling. The labeled container should be packed in cardboard or plastic containers Ampoules should be packed in partitioned boxes.

Possible time-temperature relationships:

Applications of Moist Heat sterilisation: :

Applications of Moist Heat sterilisation: Preparations and materials that can withstand the required temperatures Not sensitive to moisture Penetrated by the steam (N.B. with aqueous products water is provided by the vehicle) Generally NOT used for oils, fats, anhydrous powders

ii. Filtration:

ii. Filtration Removes most bacteria, moulds, and particles, but may allow viruses, small bacteria, and pyrogens to pass through Application: aqueous products that cannot be heat sterilized Cannot be used for suspensions or small volumes of potent drugs Only used when other methods are not suitable

iii. Ethylene Oxide:

iii. Ethylene Oxide Active against all microbes Activity depends on concentration, temperature, humidity, and length of exposure Application: Suitable for thermolabile + moisture-sensitive substances , and can sterilize a wide range of materials Disadvantages: slow, high running costs, hazards associated with flammability + toxicity, potential production of toxic substances with some materials

iv. Radiation::

iv. Radiation: Application: Tends to be used for articles not sterilisable by other methods – syringes, catheters, etc. Not usually used for pharmaceuticals as can cause destruction of product, colour changes, alterations in texture or solubility May be useful for sterilizing vaccines without loss of antigenicity

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“…Ear of bat, leg of toad, hair of dog, horn of goat…” 3. Quality Control

I. Sterility Testing:

III. Pyrogen Testing:

III. Pyrogen Testing Pyrogens are bacterial products such as endotoxin Can cause fever, activate coagulation system, alter carbohydrate lipid metabolism, produce shock and death Main source of contamination of products is water

III. Pyrogen Testing:

III. Pyrogen Testing i. LAL (limulus amoebocyte lysate) test for endotoxin Utilises extract from blood cells of horseshoe crab Contains an enzyme and protein system that clots in the presence of endotoxin

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III. Pyrogen Testing:

III. Pyrogen Testing ii. Rabbit test Based on temperature rise of rabbits compared to controls following an injection of the test product 1. Control Temperature 2. Injection of test solution 3. Record of temperature after injection

3. Quality Control:

Particulate Matter Monitoring :

Particulate Matter Monitoring

Definition: :

Definition: Unwanted mobile insoluble matter other than gas bubbles present in the given product. It may be dangerous when the particle size is larger than R.B.C. & may block the blood vessel. This type of products are immediately rejected from the batch.

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The limit test for particulate matter is prescribed in I.P. 1996 (A- 125) Applicable for: 100 ml or more volume containers of single dose LV given by IV infusion Not applicable for: Multidose injections Single dose SVP Injectable solutions constituted from sterile solids

Methods of monitoring particulate matter contamination :

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Visual method: Simple method Filled container are examined against strong illuminated screen by holding neck & rotating it slowly or inverted it to keep out the foreign matter. Coulter counter method: It is used for detection of particles less than 0.1 micrometer in diameter. Based on electrode resistance. Sample is evaluated between two electrode & if particle found the resistance of electrode is increased.

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Filtration method: It is used for counting the particles in hydraulic fluids. Sample passed thr’ filter Material is collected on filter Evaluated under microscope. Disadvantage: Skilled & trained person is required Light blockage method: Used for hydraulic oils Allows stream of fluid under test to pass between a bright white light source & photoiodide sensor.

LEAKAGE TEST:

LEAKAGE TEST Performed in vaccume chember , ampoule dipped in 1% Methylene blue dye solution When vaccume is release, colour will enter in ampoule with defective sealing presence of dye solution in ampoule confirmed leakage & hence rejected CLARITY TEST Visual inspection to exclude possibility of foreign matter for unlabeled containers Container held by neck against strong illuminated black and white screen, the content of container are slowly inverted and rotated Now a days coulter counter, photo- nephlometer

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ASSAY Performed according to method given in monograph of that parenteral preparation in the pharmacopoeia pH Very imp parameter for parenteral dosage form. IDENTIFICATION TEST As per monograph of pharmacopoeia TURBIDITY As like Heavy metal test CONTENT UNIFORMITY TEST UV analysis method/titration method WEIGHT VARIATION TEST As per Pharmacopoeia like tablet variation test

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Other solutions: Ringer injection IP Ringer lactate solution for injection IP Common uses : Used in surgery patients In replacement therapy Providing basic nutrition For providing TPN As a vehicle for other drug subs.

IV ADMIXTURES :

IV ADMIXTURES Definition: When two or more sterile products are added to an IV fluid for their administration, the resulting combination is known as IV admixture. In hospitals, prepared by nurses by combining or mixing drugs to the transfusion fluids. The drugs are incorporated in to bottles of LV transfusion fluids.

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Methods for safe & effective use of IV admixture: Proper training to nurses & pharmacist Instruction regarding labeling Information for stability & compatibility to the hospital pharmacy dept. Information for the formulation skills to the pharmacist.

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TPN stands for Total Parenteral Nutrition. This is a complete form of nutrition, containing protein, sugar, fat and added vitamins and minerals as needed for each individual. Total Parenteral Nutrition (TPN) may be defined as provision of nutrition for metabolic requirements and growth through the parenteral route. Total Parenteral Nutrition

Total Parenteral Nutrition (TPN) (Intravenous Nutrition):

Total Parenteral Nutrition (TPN) (Intravenous Nutrition) TPN refers to the provision of all required nutrients, exclusively by the Intravenous route. Parenteral Nutrition (PN)can be used to supplement ordinary or tube feeding.

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TPN might be necessary if: a patient is severely undernourished, and needs to have surgery, radiotherapy or chemotherapy; a patient suffers from chronic diarrhea and vomiting; a baby's gut is too immature; a patient's (their "gastrointestinal tract") is paralysed , for example after major surgery. Why it is necessary?

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TPN is normally used following surgery, when feeding by mouth or using the gut is not possible, When a person's digestive system cannot absorb nutrients due to chronic disease , or, alternatively, if a person's nutrient requirement cannot be met by enteral feeding (tube feeding) and supplementation. When is it necessary?

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Short-term TPN may be used if a person's digestive system has shut down (for instance by Peritonitis), and they are at a low enough weight to cause concerns about nutrition during an extended hospital stay. Long-term TPN is occasionally used to treat people suffering the extended consequences of an accident or surgery. Most controversially, TPN has extended the life of a small number of children born with nonexistent or severely birth-deformed guts.

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GENERAL INDICATIONS Patient who can’t eat Patient who won’t eat Patient who shouldn’t eat Patient who can’t eat enough “ If the gut works, use it.”

Complications of TPN:

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Dialysis is the process in which substances are separated from one another due to their difference in diffusibility (distribution) thr ’ membrane. The fluids used in dialysis are known as dialysis fluids. DIALYSIS FLUIDS

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General uses : Renal failure waste product is removed Maintain electrolytes Also called as haemodialysis or intraperitoneal dialysis Transplantation of kidney Poisoning cases

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Haemodialysis : To remove toxins from blood In haemodialysis , the blood from artery is passed thr ’ artificial dialysis membrane, bathed in dialysis fluid. The dialysis membrane is permeable to urea, electrolytes & dextrose but not to plasma proteins & lipids So excess of urea is passed out from blood thr ’ dialysis fluid. After dialysis blood is returned back to the body circulation thr ’ vein. A kidney unit may require more than 1200 litres of solution / week. So haemodialysis fluid is prepared in conc. Form then it is diluted with deionised water or dist. water before use.